Trans-1,2,3,4,4a,8,9,14a-octahydropyrido(r&#39;,3&#39;:2,3)indolo(1,7-ab)+8 1)benzazepine

ABSTRACT

The compound trans-1,2,3,4,4a,8,9,14a-octahydro-pyrido(4&#39;&#39;,3&#39;&#39;: 2,3)indolo(1,7-ab)(1)benzazepine and salts thereof, useful as analgesics. The compound is made by reacting a trans-3(substituted)-1,2,3,4,4a,8,9,14a-octahydropyrido(4&#39;&#39;,3&#39;&#39;: 2,3)indolo(1,7-ab)(1)benzazepine with a chloroformate to replace the 3-substituent group with an ester, then subjecting the resulting carbamate to hydrolysis or hydrogenolysis.

United States Patent Berger June 17, 1975 TRANS-l,2,3,4,4A,8,9,14A- I OCTAHYDROPYRIDO[4,3 ;2,3]IN- Primary ExaminerG. Thomas Todd 0 0 7- 1 p1 Attorney, Agent, or Firm-Don M. Kerr [75] Inventor: Joel G. Berger, Freeport, NY. [73] Assignee: E l. r lu Pont de Nemours & C0., [57] ABSTRACT Wilm1ngton,.Del. y I 11, 19 The compound trans-l,2,3,4,4a,8,9,l4a-octahydro- [22] May 73 pyrido[4',3':2,3]indolo[ l,7-ab][l]benzazepine and pp 359,504 salts thereof, useful as analgesics. The compound is made by reacting a trans-3-(substituted)- 1 2 3,4 4a 8 9 14a-octah dro rid0[4,3':2 31in- 5 U.S. Cl 260 293.55, 260 240 K, 424 267 y Int Cl C07d 5/7/04 d0lo[l,7-ab][1]benzazepine wlth a chloroformate to [58] Fieid 260/293 55 replace the 3-substituentgroup with an ester, then subjecting the resulting carbamate to hydrolysis or by- [56] References Cited drogenolysls' 4 Claims, N0 Drawings 1 TRANS-1 ,2,3,4,4A,8 ,9,14A- OCTAHYDROPYRIDO[R' ,3 :2,3]INDOLO[1,7- AB] [1]BENZAZEPINE BACKGROUND OF THE INVENTION This invention relates to octahydropyridoindolobenzazepines.

Certain octahydropyridoindolobenzazepines are known from U.S. Pat. Nos. 3,373,168 and 3,457,271, assigned to Hoffmann-LaRoche, Inc. Those compounds can be represented according to the abovementioned patents by the following Formula (1):

wherein R is a straight chain or branched alkyl having l-7 carbon atoms.

According to the IUPAC 1957 Rules, the same compounds are represented by the formula:

and are named 1,2,3,4,4a,8,9,14aoctahydropyrido[4,3:2,3]indolo[ 1,7-

ab][ 1 ]benzazepines. The IUPAC representation and nomenclature will be used herein.

The compounds of Formula (1) are said in U.S. Pat. Nos. 3,373,168 and 3,457,271 to have antidepressant activity and to be useful antidepressant agents. These compounds are prepared according to the above two patents by reduction of the corresponding hexahydro compounds either with sodium in a mixture of tetrahydrofuran and liquid ammonia or with zinc in hydrochloric acid. The former method is preferred by the patentees since it gives higher yields.

U.S. application of C. D. Adams, Ser. No. 325,352, filed Jan. 22, 1973, discloses l,2,3,4,4a,8,9,14aoctahydropyrido[4,3':2,3]indolo[1,7- ab][1 ]benzazepines which can be represented by structural formula I wherein R is C C alkyl, C C cycloalkyl, C -C cycloalkylmethyl, exo-7- norcarylmethyl, benzyl or phenethyl. The compounds of the application have a different steric configuration of the hydrogen atoms at the 4a and 14a positions from those of the above patents. The evidence is that the compounds of the application have the transconfiguration of the 4a and 14a hydrogens and that the compounds of the above patents have the cis configuration. The compounds of the application are made by reducing the corresponding hexahydro compounds with boron hydride/tetrahydrofuran complex in tetrahydrofuran or diethyleneglycol dimethyl ether, and are useful as CNS depressants and analgesics.

U.S. application of H. Blumberg, Ser. No. 245,300, filed Apr. 19, 1972, discloses I,2,3,4,8,9- hexahydropyrido-[4,3':2,3]indolo[1,7- ab][ 1 ]benzazepine and its use as an analgesic.

Attempts to prepare trans-l ,2,3,4,4a,8,9,14aoctahydropyrido[4',3:2,3]indolo[1,7- ab][ 1 ]benzazepine by reducing the corresponding hexahydro compound of the Blumberg application according to the method of the Adams application were not successful.

SUMMARY OF THE INVENTION This invention includes the compound trans- I,2,3,4,4a,8,9,14a-octahydropyrido[4,3:2,3]indolo[ l ,7-ab][ l ]benzazepine and its addition salts with pharmaceutically suitable acids, pharmaceutical compositions containing the compound or a salt thereof and use of the compound and its salts as analgesics. The invention also includes a method of making the compound starting with a trans-3-(substituted)- l,2,3,4,4a,8,9,l4a-octahydropyrido[4',3':2,3]in dolo[ l,7-ab][1]benzazepine, and a novel class of compounds of the formula:

wherein R is C C. alkyl, vinyl, benzyl, p-methylbenzyl, p-

methoxybenzyl or phenyl and the hydrogens in the 4a and 14a positions are in trans relationship to each other, which are useful as intermediates in the process.

DESCRIPTION OF THE INVENTION The compound trans-l,2,3,4,4a,8,9,14aoctahydropyrido[4,3 ':2,3]indolo[ 1,7- ab][ 1 ]benzazepine can be made by the following process:

a. reacting a trans-3-(substituted)- 1,2,3 ,4,4a,8,9, 1 4a-octahydropyrido[4 ,3 ':2,3]indolo[ l,7-ab][ l ]benzazepine of the formula or Pl /cat 30 mers of The quaternary ammonium salt initially produced upon reaction with the chloroformate is not isolated. The intermediate compound (formula 2) can but need not be isolated. The reaction with the chloroformate can be carried out at a temperature in the range of 20 to l 10C., preferably 80 to 1 10C., in an inert organic solvent such as benzene, toluene or dioxane.

Hydrolysis of the compound of formula 2 can be carried out in a C C alkanol containing 0-10% water and a hydroxide of potassium, sodium, lithium or calcium, at a temperature in the range of 65140C. Alternatively, it can be carried out in aqueous mineral acid (e.g., acetic acid or hydrochloric acid) at a temperature in the range of 20-110C. The hydrogenolysis, applicable when R is benzyl or substituted benzyl,

can be carried out with 1-3 atmospheres hydrogen pressure, a temperature in the range of 3060C. and a platinum, palladium or Raney nickel catalyst.

Representative pharmaceutically suitable acids which can be used to make the acid addition salts of this invention are the following: hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic, citric, pamoic, succinic, methanesulfonic, ethanedisulfonic, acetic, propionic,

tartaric, salicylic, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, and toluenesulfonic.

This invention includes the optically active enantiotrans-l,2,3,4,4a,8,9,l4aoctahydropyrido[4',3:2,3]ind0lo[1,7- ab][ 1 ]benzazepine and the intermediate compounds of formula (2), as well as the racemic mixtures.

EXAMPLE 1 A. Preparation of the Starting Material A mixture of 24.6 g of N-aminoiminodibenzyl (5- amino-l0,l l-dihydro-5H-dibenz[b,f]azepine) and 14.8 g of 4-piperidone hydrochloride in 250 ml. ethanol was heated on a steam bath for minutes and cooled; a solution of g. of concentrated sulfuric acid in 250 ml. ethanol was added. The resulting mixture was reheated on the steam bath for an additional 40 minutes; the solution which formed was cooled, basified with ammonia, and diluted with 1 liter of water. The crude, semisolid material which separated was taken up in ether, and the aqueous mother liquors were extracted with additional portions of ether. The combined ethereal extracts were concentrated to 500 ml. and treated, under an atmosphere of nitrogen and with vigorous stirring, with 50 ml. of 5N hydrochloric acid. The resulting precipitate was filtered off, washed with ether and 1N hydrochloric acid, and dried in vacuo at 100 to yield 1,2- ,3,8,9-hexahydropyrido[4',3 :2,3 ]indolo[ l,7- ab][ 1 ]benzazepine hydrochloride, m.p. 309, a salt only very slightly soluble in water. Dissolving the above salt in aqueous acetic acid, basifying with ammonia, filtering off the crude product and recrystallizing it from benzene regenerated the free 1,2,3 ,4,8,9- hexahydropyrido[4,3 :2,3 ]indolo[ l,7- ab][ 1 ]benzazepine, m.p. l34l36C.

To a solution of 16.4 g of l,2,3,4,8,9-

hexahydropyrido[4,3':2,3]indolo[1,7-

ab][ 1 ]benzazepine in 500 ml. of dichloromethane, 7.3 g. of cyclopropanecarbonyl chloride was added, followed by dropwise addition of 10 ml. of triethylamine. A mildly exothermic reaction took place, after which stirring of the mixture was continued at room temperature overnight. The mixture was then washed with 1N hydrochloric acid and water and dried over anhydrous sodium carbonate. On evaporation to dryness, crude 3-(cyclopropylcarbonyl l ,2,3,4,8,9- hexahydropyrido]4 ,3 ':2,3]indolo[ l,7-

ab] [1]benzazepine was obtained as a glassy product. Recrystallization from ethanol yielded the pure material, mp. 154-156C.

A solution of 8.6 g. of the above compound in 120 ml. of tetrahydrofuran was added dropwise to a suspension of 2.3 g. of lithium aluminum hydride in 180 ml. of tetrahydrofuran. On completion of the addition, the mixture was first refluxed for four hours, then allowed to stir at room temperature overnight and finally decomposed in the usual manner. After filtering off the inorganic salts, the filtrate was dried over anhydrous sodium carbonate and evaporated in vacuo; the residue was dissolved in a 1:1 mixture of ethyl acetate-benzene and chromatographed on a 14 X 2.2 cm. column of basic alumina, activity I. The eluate was taken down to dryness; the residual oil dissolved in absolute alcohol, saturated with ethanolic hydrogen chloride, and once again evaporated to dryness. Upon crystallization of the residue from acetone, 3-(cyclopropylmethyl)- l,2,3,4,8,9-hexahydropyrido[4,3':2,3]indolo[ l,7- ab][l]benzazepine hydrochloride, m.p. 267, was obtained.

A solution of 9.25 g. of the free base of the above hexahydro compound in 75 ml. of tetrahydrofuran was added drop-wise to a stirred lN solution of boron hydride in tetrahydrofuran (100 ml.) under a nitrogen blanket. After the addition was complete, the mixture was refluxed under nitrogen for five hours, then cooled in ice and quenched with 20 ml. of 6N hydrochloric acid. The mixture was distilled, the removed liquid being from time to time replaced by addition of dioxane. The mixture was again refluxed at 91C. for one hour with additional 6N hydrochloric acid, then cooled to C., made basis with sodium hydroxide, and evaporated in vacuum. The semisolid residue was treated with water and chloroform, and the chloroform layer was further worked up to yield (+)-trans-3- (cyclopropylmethyU-l ,2,3,4,4a,8,9, 1 4aoctahydropyrido[4',3 :2,3 ]indolo[ l,7-

ab][ 1 ]benzazepine, m.p. l52.5l55 after recrystallization from ether.

B. Preparation of Final Product A solution of 4.2 ml. of ethyl chloroformate in 35 ml. dry benzene was added to a solution of 3.9 grams (+)-trans-3-(cyclopropylmethyl)-'l,2,3,4,4a,8,9,l4aoctahydropyrido[4,3 :2,3]indolo[ l ,7- ab][ 1 ]benzazepine in ml. dry benzene. The stirred solution was heated to reflux whereupon a white precipitate formed. Heating at reflux was continued for 3 /2 hours and the reaction mass was cooled and filtered; 0.43 grams of solids were collected. Filtrate was evaporated to dryness leaving a heavy yellow oil. This was dissolved in 100 ml. n-butanol, 10 grams KOH pellets were added and the mixture was stirred at reflux for 1 hour. The mass was then cooled and concentrated and the residue was partitioned between toluene and water. The toluene solution was then extracted with water until the extracts were neutral, then the toluene solution was extracted four times with 100 ml. of 2N aqueous tartaric acid. The combined extracts were washed once with ether then basified with sodium hydroxide. The oily product was extracted twice into methylene chloride. The combined extracts were washed and dried over potassium carbonate. The solution was then filtered and evaporated to get a pale, yellow oil which crystallized under pentane. Recrystallization from about 50 ml. hexane/benzene gave 1.68 grams (+)-trans- 1 ,2,3,4,4a,8,9, l 4a-octahydropyrido[4',3 :2,3]indolo[ l,7-ab][ l ]benzazepine, yellow crystals melting point l48.5l49.5C.

The mother liquors from above were evaporated to dryness, dissolved in ethanol, then treated with excess tartaric acid in ethanol. A yellow oil formed which on heating at reflux in ethanol gave a white solid, the tartrate of (+)-trans-l,2,3,4,4a,8,9,l4aoctahydropyrido[4,3 :2,3 ]indolo[ l ,7- ab][l]benzazepine, m.p. 255256C. (dec.).

Similarly, treatment of the mother liquors with ethanolic HCl provides the corresponding hydrochloride, m.p. 325C.

EXAMPLE 2 A suspension of 70 grams of (+)-trans-3- (cyclopropylmethyl )-l ,2,3,4,4a,8,9, 14aoctahydropyrido[4,3 ':2,3]indolo[ l ,7- ab][ 1 ]benzazepine in 500 ml. dry benzene was heated with a solution of 83 ml. ethyl'chloroformate in 250 ml. benzene. The solution was then heated at reflux for 3 /2 hours, solids were filtered off (6.2 grams) and the filtrate was evaporated to give an oil which began to solidify. Recrystallization from 600 ml. ethanol gave 53.4 grams ethyl (+)-trans-1,2,3 ,4,4a,8 ,9, 1 4aoctahydropyrido[4,3 :2,3 ]indolo[ l,7- ab][1]benzazepine-3-carboxylate as a white solid, melting point l46.5l49C.

The recrystallized ester was added to a solution of 60 grams KOH in 500 ml. n-butanol. The solution was heated 2 hours at reflux. The reaction mass was then cooled and concentrated to about one-half volume, then treated with toluene and water. The toluene layer was washed with water until the extracts were neutral. The toluene layer was then extracted with six portions of 250 ml. 1M tartaric acid in water. The combined extracts were then extracted once with ether, then cooled and basified to pH greater than 1 l with 50% sodium hydroxide. This caused formation of a precipitate. The material was then extracted with several portions of CH Cl The extracts were combined, washed with water, dried over K CO filtered, and evaporated to give an oil. This oil was taken up in about 75 ml. benzene and the mixture was then diluted with about 300 ml. hexane. The solution was held at 4C. overnight and crystallization occurred. The crystals were filtered, washed with benzene/hexane and dried. The product was 26.9 grams of (+)-trans-l,2,3,4,4a,8,9,14aoctahydropyrido[4,3 :2,3]indolo[ l ,7- ab][ 1 ]benzazepine in the form of yellow crystals with melting point l48l49C.

The following tests are recognized standard methods for determining analgetic activity of test compounds.

Phenylquinone Writhing (POW) Groups of at least mice are given phenyl-pbenzoquinone 2.5 mg/kg intraperitoneally minutes after oral administration of graded doses of the test substance. Two or more dose levels are used for each compound. For scoring purposes, a writhe is defined as stretching, twisting of a hindleg inward, or contraction of the abdomen. The total number of writhes for each animal, treated and control animals side-by-side, are counted over a 30-minute time interval. An ED calculated on basis of the percentage of animals at each dose level which showed 50% or less of the average number of writhes of the control animals, is reported for each compound submitted to this screening test.

Mouse Hot Plate Groups of eight mice are observed at six predetermined intervals during the first hour after oral administration of graded doses of test substance. Two or more dose levels are used for each compound. Animals are observed at each time interval by placing them on a hot plate, maintained at i O.5C., until they show dis comfort, but in any case for no longer than 30 seconds. Discomfort is manifested by animals picking up a hindpaw, picking up a paw and licking it, or by animals jumping off the plate. Each animal serves as its own control, and where the time of reaction to discomfort of the treated animal exceeds the time of reaction prior to treatment by 5 seconds, analgesia has been effected for the purpose of this test. An ED calculated on basis of the percentage of animals at each dose level displaying analgesia, is reported for each compound tested by this method.

The results in these tests for (+)-transl,2,3,4,4a,8,9,l4a-octahydropyrido[4',3:2,3]indolo[ l,7-ab][ l ]benzazepine (compound A) and codeine phosphate were as follows:

ED in mg/kg p.o. mouse Many analgesic compounds show other actions of general central nervous system depression, such as sedation or muscular weakness. Such side effects are usually undesirable and sometimes prohibitive. The compound (+)-trans-l,2,3,4,4a,8,9,l4aoctahydropyrido[4,3':2,3 ]indolo[ l ,7- ab] l ]benzazepine in animal tests has shown very little indication of the other types of general central nervous system depression or side effect.

The compound trans l ,2,3,4,4a,8,9,14aoctahydropyrido[4,3':2,3]indolo[ l ,7- ab][l]benzazepine and some of its pharmaceutically suitable inorganic or organic acid addition salts are substantially insoluble in water. They are best administered orally at a level of about 1 to about 100 mg. per kilogram of body weight of the animal. Some of the addition salts are more water soluble and can be administered by subcutaneous or intramuscular injection. The dosage employed in such case is generally within the range of 0.3 to about 15 milligrams per kilogram of body weight.

The pharmaceutical compositions of this invention consist essentially of the compound transl,2,3,4,4a,8,9, l 4a-octahydropyrido[4,3 :2,3 ]indolo[ l,7-ab][ l ]benzazepine or an acid addition salt thereof and a pharmaceutically suitable carrier. The carrier may be either a solid or liquid and the compositions can be in the form of tablets, liquid filled capsules, dry filled capsules, aqueous solutions, non-aqueous solutions, suppositories, syrups, suspensions and the like. The compositions can contain preservatives, coloring and flavoring agents. Some examples of the carriers which can be used in the preparation of the compositions are: gelatin capsules, sugars such as lactose and sucrose, starches, dextrans and cellulosics, such as methyl cellulose and cellulose acetate phthalate, gelatin; talc; stearic acid salts; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; liquid petrolatum; polyethylene glycol; glycerine; sorbitol; propylene glycol; ethanol; agar; water and isotonic saline. The expression consisting essentially of is used to indicate that in addition to the ingredients specifically recited, i.e., the essential ingredients, the compositions can contain other ingredients provided they do not interfere with the intended use of the compositions.

The concentration of the active ingredient and the pharmaceutical carrier may vary for each dosage form. The ordinary range for tablets and capsules is 10-90% by weight of the active ingredient and 10% of the carrier. For the liquid dosage form, such as syrups, suspensions and injections, the concentration is ordinarily between 0.1 and 10% by weight of active ingredient and the corresponding 99.990% of the vehicle.

Typical formulations of the type mentioned above are:

All of the above ingredients are passed through a suitable sieve, blended for 20 minutes, and compressed directly into tablets of 200 mg. on a suitable tablet press using a 11/32 inch punch and die.

The combined ingredients are blended and passed through a 40 mesh sieve, and the mixture is encapsulated into a a two-piece hard gelatin No. 3 capsule on a suitable encapsulating machine at a net weight of 128 mg.

Example C Ingredients gram/ liter l,7-ab][ l ]benzazepine methanesulfonate propylparaben, USP

methylparaben, USP

sodium carboxymethylcellulose, USP (CMC) polysorbate 80, USP

Water for Injection l q.s. to l liter The parabens, CMC and one-half of the polysorbate 80 are dissolved in about 700 ml. of Water for Injection, with agitation at 80 (solution A). A slurry is made of the active ingredient, one-half of the polysorbate 80 and about 200 ml. of Water for Injection (slurry B). Solution A is aseptically filtered through a Millipore filter to render it sterile, while slurry B is autoclaved for 30 minutes at 15 lbs. steam pressure to make it sterile. A and B are aseptically combined, brought to correct volume with sterile Water for Injection, and mixed to homogeneity.

I claim:

1. Trans-l ,2,3,4,4a,8,9,14aoctahydropyrido[4',3 ':2,3]indolo[ 1,7- ab][ 1 ]benzazepine and acid addition salts thereof with pharmaceutically suitable acids.

2. A compound of the formula:

COOK

3 N. 2 f \In 1-z1 a (2) ll 1 3 1-; x2 N i s a a l 0 7 wherein R is C -C alkyl, vinyl, benzyl, p-methylbenzyl, p-

methoxybenzyl or phenyl and the hydrogens in the 4a and 14a positions are in trans relationship to each other. i

3. Compound of claim 2 wherein R is ethyl.

4. A method of making the compound of claim 1 which comprises:

a. reacting a trans-3-(substituted)- 1,2,3 ,4,4a,8,9, l 4a-octahydropyrido[4 ,3 :2,3 ]indolo[ l,7-ab][ I ]benzazepine of the formula (:H. H l 2 H 

1. TRANS-1,2,3,4,4A,8,9,14AOCTAHYDROPYRIDO(4'',3'':2,3)INDOLO(1,7 -AB)(1)BENZAZEPINE AND ACID ADDITION SALTS THEREOF WITH PHARMACEUTICALLY SUITABLE ACIDS.
 2. A compound of the formula:
 3. Compound of claim 2 wherein R is ethyl.
 4. A method of making the compound of claim 1 which comprises: a. reacting a trans-3-(substituted)-1,2,3,4,4a,8,9,14a-octahydropyrido(4'',3'':2,3)indolo(1,7-ab)(1)benzazepine of the formula 